Bakgrund: Övervikt och fetma ökar exponentiellt i alla samhällsklasser i alla delar av världen idag. Det kan orsaka lidande och förtida död för de drabbade. Risken att drabbas av våra vanligaste vällevnadssjukdomar som hjärt- och kärlsjukdom, typ 2 diabetes och neurodegenerativa sjukdomar som Alzheimers sjukdom ökar vid övervikt och fetma. Det i särklass mest effektiva sättet att gå ned i vikt är genom att minska sitt kaloriintag. För att behålla en viktnedgång behövs beteendeförändringar, stöttning och en långsiktig plan. Syfte: Syftet med studien är att undersöka om intermittent kalorirestriktion (CR) är mer effektivt än kontinuerlig CR när det gäller viktreduktion och bibehållande av ny vikt. Metod: En litteraturstudie genomfördes där fyra olika parallellstudiers resultat sammanställs. Parallellstudierna jämför effektiviteten av intermittent och kontinuerlig CR på viktreduktion och bibehållande av ny vikt. Resultat: I tre av de fyra studier som undersökts kan inga skillnader i effektivitet uppvisas mellan intermittent och kontinuerlig CR när det gäller viktreduktion och bibehållande av ny vikt över tid. En av studierna fann att intermittent CR, i form av ”week on, week off” två veckor i taget är mer effektiv när det gäller viktreduktion efter 16 veckors interventionsfas samt 6 månader senare. Slutsats: Som alla metastudier jag läst och de flesta studier på ämnet kan ingen skillnad i effektivitet mellan intermittent och kontinuerlig CR uppvisas gällande viktreduktion. Inte heller verkar den ena vara överlägsen den andra när det gäller bibehållande av ny vikt. Fler studier över längre tidsspann med fler deltagare krävs för att kunna dra slutsatser om vilken typ av CR som är mest effektiv på lång sikt. / Background: Overweight and obesity are increasing exponentially in all social classes in all parts of the world today. It can cause suffering and premature death to those affected. The risk of suffering from our most common well-being diseases such as cardiovascular disease, type 2 diabetes and neurodegenerative diseases such as Alzheimer's disease increases with overweight and obesity. By far the most effective way to lose weight is by reducing your calorie intake. To maintain a weight loss, behavioural changes, support and a long-term plan are needed. Purpose: The purpose of the study was to investigate whether intermittent calorie restriction (CR) is more effective than continuous CR in terms of weight reduction and maintenance of new weight. Method: A literature study was conducted where the results of four parallel studies were put together. The parallel studies compare the effectiveness of intermittent or continuous CR on weight reduction and maintenance of new weight. Result: In three of the four studies examined, no differences in effectiveness can be demonstrated between intermittent and continuous CR in terms of weight reduction and maintenance of new weight over time. One of the studies found that intermittent CR, in the form of "week on, week off" two weeks at a time, is more effective in weight reduction after 16 weeks of intervention and 6 months later. Conclusion: Like all meta-studies and most studies on the subject, no difference in effectiveness between intermittent and continuous CR can be demonstrated in terms of weight reduction. Nor does one seem superior to the other when it comes to maintaining new weight. More studies over longer time spans with more participants are required to be able to draw conclusions about the type of CR that is most effective in the long term.

Obese, female Spraque-Dawley rats were assigned, on a weight basis, to one of three dietary treatments: ad lib, 15% caloric restriction, and 30% caloric restriction. All other nutrients were fed at levels to meet dietary requirements. Each treatment groups was further sub-divided into pregnant and non-pregnant animals. Rats were sacrificed on Day 20 of gestation and fetuses were taken by Caesearean section. Maternal and fetal body composition, maternal serum protein concentrations were examined. Weight change for pregnant rats was +85 gms in the ad lib-fed group, +82 gms in the 15% calorie restricted group, and +56 gms in the 30% calorie restricted group. Weight changes for the non-pregnant rats for 20 days of dietary treatment were +53 gms, +18 gms, and -7 gms respectively. Fetal body nitrogen and average pup weight did not differ between treatment groups. Total maternal body nitrogen was not decreased during pregnancy in ad lib-fed and 15% calorically restricted animals. It did decrease in 30% calorically restricted animals. Ad lib-fed animals showed no changes in total body fat. Animals on the 15% calorie restriction diet showed no change in total body fat percentages. Animals on the 30% calorie restriction showed a 10% decrease in total body fat content as compared to the ad lib and 15% restricted pregnant group. Serum protein levels decreased in pregnant animals as caloric restriction increased. Serum protein levels in nonpregnant animals increased as dietary restriction increased. The fetal compartment was not affected by maternal caloric restriction up to 30% provided that all other nutrients were adequate. Maternal stores were affected at a level of 30% caloric restriction. / Master of Science

Obese female Sprague Dawley Rats were randomly assigned, on a weight basis, to one of three dietary treatments: ad libitum, 30% caloric restriction, and 50% caloric restriction. All other nutrients were fed at levels to meet dietary requirements. Each treatment group was further divided into pregnant and nonpregnant subgroups. The experimental diets were started on Day 4 of gestation for pregnant groups. Rats were sacrificed on Day 20 of gestation and fetuses were taken by Caesarean section. Maternal and fetal body composition, and the maternal serum protein concentration were examined. Weight changes for pregnant rats were +127 gms in the ad lib fed group, +83 gms in the 30% restricted group, and +51 gms in the 50% restricted group. Weight changes for the nonpregnant rats after 20 days of dietary treatment were +22 gms, -10 gms, and -40 gms in the ad lib fed, 30%, and 50% restricted groups respectively. The percentage of maternal carcass protein was affected by the 50% caloric restriction imposed on all animals. Animals on the 30% and 50% caloric restricted diet showed a decrease in total body fat of 5% and 12% respectively, as compared to the ad lib fed controls regardless of pregnancy state. The maternal liver weight increase during pregnancy was less in 30% and 50% caloric restricted animals. Serum protein levels decreased in pregnant animals as caloric restriction increased. Fetal body weight, brain weight, and body composition did not differ between treatment groups. The fetal compartment was not affected by maternal caloric restriction up to 50% while providing all other nutrients adequately. Maternal stores were affected at both levels of 30% and 50% caloric restriction. These results indicate that excess fat stores can be mobilized to support fetal growth in obese pregnant rats under caloric restriction, when other nutrients are provided in adequate amounts. / M.S.

<p dir="ltr">As obesity is a pressing public health issue in the U.S., policymakers and health advocates continue to seek ways to improve consumers’ dietary behaviors. One challenge is the prominence of food away from home (FAFH) spending among U.S. households. FAFH meals are typically more calorically dense and nutrient poor. To further complicate this, there has been a substantial rise in the use digital food ordering and delivery systems, yet little is known about consumer ordering behavior on these platforms. While hunger is a key driver for eating, FAFH is also influenced by other factors, including biological (appetite, taste), economic (cost, income), psychological (mood, stress), and social factors (peers). Existing research has highlighted the significant impact of peer influence on decision-making regarding food consumption. However, the context of online food ordering presents unique challenges due to limited peer interaction. Thus, to study the peer effect in online food ordering, we conducted an online experiment. We simulated an online restaurant ordering experience and asked respondents to place a food order at a hypothetical restaurant. Respondents were randomly assigned to one of five treatments that told them how many calories an average peer ordered from the restaurant (800, 1200, 1600, 2000 calories, or a control treatment with no peer information). We examine the potential for peer effects on total calories ordered and the likelihood of ordering from different menu categories (e.g., appetizer, entrée, side, dessert, beverage) as well as calories ordered from them. Our study revealed that people adjust their calorie intake based on their peers' online food orders. The influence depends on the individual's calorie intake levels. Appetizers, entrée, and dessert calorie count showed a consistent pattern in response to peer, although the effect on desserts is not significant. Additionally, people tend to choose a greater variety of items when they have information about their peers' orders. These findings underscore the importance of considering peer influence in the design of online food-ordering platforms and related policies, emphasizing the need for tailored interventions to address dietary behaviors in digital environments.</p>

Tannine sind pflanzliche, polyphenolische Sekundärmetabolite mit Protein-präzipitierenden und –bindenden Kapazitäten, welche offenbar für die antinutritiven und gesundheitsschädlichen Wirkungen der Tannine verantwortlich sind. Jedoch dominieren in der Literatur die gesundheitsfördernden Beschreibungen, für die meist die antioxidative Kapazität verantwortlich gemacht wurde. Der etablierte Modelorganismus Caenorhabditis elegans wurde zur Analyse dieses Kontrastes ausgewählt. Zunächst wurden Lebensdauer und Stressresistenz der mit Tanninsäure und den Tanninbausteinen Gallussäure, Ellagsäure und Catechin behandelten Nematoden ermittelt. Das vermutete Vorliegen eines „Calorie Restriction“ (CR)-Effektes als auch einer hormetischen Dosis-Wirkungs-Beziehung wurde überprüft. Weiterhin wurden antimikrobielle und antioxidative Eigenschaften als potentielle Ursachen der Langlebigkeit untersucht und die Auswirkungen auf die Fitness und Genexpression analysiert. Die Einbeziehung verschiedener Alterungs-Theorien rundete die Analyse der Tanninwirkung ab. Alle Tannin-Substanzen konnten eine Lebensverlängerung erwirken, doch erstaunlicherweise erwiesen sich Langlebigkeit und Stressresistenz als individuelle, nicht zwangsläufig gekoppelte Parameter. Hormesis, CR-nachahmende Eigenschaften, antimikrobielle Kapazitäten als auch verschiedene stressrelevante Gene sind teilweise für die Lebensverlängerung verantwortlich. Die antioxidative Kapazität scheint jedoch irrelevant zu sein. Die differentielle Expression mehrerer hundert Gene durch Tanninsäure unterstreicht zudem die Komplexität der Wirkweise. Hinweise zur Bestätigung der „Disposable Soma Theory“, der „Mitohormesis“-Theorie und der „Green Theory of Ageing“ konnten zum Teil gefunden werden. Diese Arbeit zeigt die individuelle und kontrastreiche Wirksamkeit der Tannine auf. Sie unterstreicht, dass Tannine molekulare Regulatoren sind, welche nicht nur auf ihre antioxidative und antinutritive Kapazität reduziert werden sollten. / The polyphenolic tannins are plant-produced secondary metabolites with protein precipitating and binding capacities. This characteristic is seemingly responsible for antinutritional and harmful effects. However, health benefits have also been extensively described in the literature. Indeed, antioxidant properties are believed to be the reason for these beneficial effects. The established model organism Caenorhabditis elegans was chosen to examine this apparent contradiction. The nematodes were exposed to tannic acid and to the tannin building blocks gallic acid, ellagic acid, and catechin and the lifespan and stress resistance were determined. The presence of a calorie restriction (CR) effect and a hormetic dose-response-relationship was verified. Furthermore, antimicrobial and antioxidative capacities were assessed as possible causes of longevity and the impact on fitness parameters and gene expressions was analysed. The consideration of different ageing theories completed the analysis of the tannin action. All tannin-substances were able to prolong the lifespan but against all expectations, longevity and stress resistance were shown to be independent entities, which are not necessarily linked. Hormesis, CR-mimetic properties, antimicrobial capacities as well as several stress relevant genes are partly responsible for the life-extension. The antioxidant capacities, however, appeared to be irrelevant. The regulation of several hundred gene expressions by tannic acid underlined the complexity of the mode of action. Furthermore, the results partly confirm the “Disposable Soma Theory”, the “Mitohormesis Theory” and the “Green Theory of Ageing”. This work dissects the contrasting efficiency of the tannin family and underlines in particular, that tannins are molecular regulators, which should not be reduced to their antioxidative and antinutritional capacities

2 pp. / The energy content of food is measured in calories. The number of calories, or energy, an athlete needs to maintain weight depends upon: age, body weight, gender, Resting Energy Expenditure (REE) and physical Activity Energy Expenditure (AEE) levels.

Mudanças no hábito alimentar têm sido descritas como prováveis causas da obesidade. Estudos mostram que o peso depende do balanço energético definido pela relação entre a energia ingerida e o gasto energético. Sugere-se que o padrão alimentar, levando em consideração a freqüência de refeições e sua distribuição durante o dia, possa estar relacionado com a obesidade. Um efetivo programa de perda de peso tem como objetivo a perda do excesso da gordura corporal e a manutenção da massa livre de gordura apropriada para manutenção da saúde. O cortisol é um dos principais hormônios secretados pelo córtex supra-renal com ação predominante no metabolismo intermediário, incluindo a regulação das proteínas, carboidratos, lipídeos e ácidos nucléicos.O presente estudo teve como objetivos determinar se a ingestão alimentar hipocalórica em pacientes obesas grau III, feita exclusivamente no período das 9:00 às 11:00 h em contraposição à mesma dieta oferecida das 18:00 às 20:00 h, é capaz de alterar a perda de peso, a composição corporal, o ritmo de cortisol, o gasto energético e o balanço nitrogenado. As pacientes foram internadas na Unidade Metabólica da Divisão de Nutrologia do Departamento de Clínica Médica do Hospital das Clínicas de Ribeirão Preto USP durante um período de 64 dias, sendo divididos em 3 internações de 18 dias. Na 1ª fase receberam dieta fracionada em 5 refeições /dia, considerada controle. Na 2ª fase, receberam a mesma dieta, no período das 9:00 às 11:00 h. E na 3ª fase receberam, também, a mesma dieta no período das 18:00 às 20:00 h. Entre uma internação e outra, as pacientes tiveram alta hospitalar por 5 dias, recebendo dieta domiciliar usual. Durante cada fase realizou-se dosagem de nitrogênio urinário e de cortisol salivar. Além disto, as pacientes foram submetidas à avaliação nutricional incluindo: antropometria, bioimpedância e calorimetria indireta. O cortisol salivar obedeceu ao mesmo ritmo nas 3 fases, tanto no 1º quanto no 18º dias de internação, apresentando o pico máximo às 8:00 h, diminuindo progressivamente até atingir o nadir às 21:00 h. Não houve alteração no ritmo do cortisol quando se alterou o horário da alimentação. Houve uma diminuição significativa (p< 0,05) para todos os parâmetros antropométricos, exceto para o índice cintura/quadril durante as três fases, não havendo diferença entre as 3 fases. Houve, nas 3 internações, uma diminuição significativa tanto na quantidade de nitrogênio ingerido quanto na quantidade de nitrogênio excretado a partir do 4º dia de internação. No 10º dia de internação, o balanço nitrogenado estava negativo nas 3 fases da dieta. Não houve diferença entre as fases para ingestão, excreção ou balanço nitrogenado. Mudanças no padrão do horário da ingestão alimentar por períodos de 18 dias não foram estímulo suficiente para provocar diferentes alterações de peso, da composição corporal, da ritmicidade e níveis de produção de cortisol, da taxa metabólica de repouso e balanço nitrogenado em mulheres grau III. / Changes in dietary habits have been implicated as potential causes of obesity. Studies have suggested that weight depends on the energetic balance, which is the relation between energy intake and energy expenditure. Dietary behavior, specially eating frequency and temporal distribution of eating events during the day, may be related to obesity. An effective weight loss program should reduce body fat and preserve lean body mass. Cortisol is an important corticosteroid produced by the adrenal. It exerts metabolic effects on intermediary metabolism, regulating protein, carbohydrates, lipids and nucleic acids metabolism. The present studys goals were: compare differences in weight loss, body composition, energy expenditure and nitrogen balance using hypo caloric diet offered in two different time intervals, first from 9:00 to 11:00, second from 18:00 to 20:00; determinate if there is difference on urinary nitrogen when food is offered on different time intervals, comparing with salivary cortisol levels, and show salivary cortisol secretion rhythm of obese females undergoing hypo caloric diet in different day times. The patients were under hospital regimen in the Metabolic Unit of the Nutrology Division of the Internal Medicine Department of the HCFMRP USP for a 64 days period, divided in 3 periods of 18 days each. On phase 1, the patients received food five times a day. On phase 2, they received the same diet, but the meals were between 09:00 and 11:00. On phase 3, the same diet was offered between 18:00 and 20:00. After each 18 day period, patients went home for a 5 day wash-out period, eating their regular home food and respecting their usual dietary behavior. On each phase urinary nitrogen and salivary cortisol were measured. Also a nutritional evaluation, including anthropometry, bioimpedance and indirect calorimetry were done. There were a reduction (p< 0,05) in all parameters, except the Waist/ Hip Ratio during all phases, but there were no difference between the phases. On the 3 phases there were a reduction on both, nitrogen intake and excretion. After the 10th in hospital day, nitrogen balance was negative on the 3 phases. There are no differences on nitrogen intake, excretion or balance between the 3 phases of food intake. Salivary cortisol followed the same rhythm on all 3 phases, both on the 1st and on the 18th in hospital days, having the peak salivary level at 08:00 h and the nadir level at 21:00 h. Changing meal times for 18 days did not change salivary cortisol circadian rhythm and did not promote changes in weight loss, body composition and rest energy expenditure in grade III obese females.

非傳染性疾病是目前全球最常見的疾病之一。不健康的食相信是導致非傳染性疾病增加的主要因素之一。因此，我們就食對乳腺癌的形成和膽固醇代謝調控的影響進行了研究。 / 在去除卵巢的祼鼠模型中，我們研究了長期和短期熱量限制對乳腺癌腫瘤增殖的影響。14週齡的小鼠被隨機分為5組：自由攝食組 (AL)；熱量攝入控制在AL80% 的20%CCR組；熱量攝入控制在AL的70% 的30%CCR組；熱量攝入控制在AL的65% 的35%CCR組和短期熱量限制 （SCR）組 (前3.5週熱量攝入控制在AL的65%，之後的13.5週自由攝食)。10週後，熱量限制組的腫瘤體積明顯較AL組小 (P < 0.05)。排除攝食對體重的影響，SCR組的腫瘤重量明顯較AL組小 (P < 0.05)。本實驗結果表明，在此動物模型中，短期熱量限制能有效抑制乳腺癌細胞的增殖。 / 此外，我們還研究了芹菜素在肝細胞中對膽固醇代謝的影響。芹菜素是一種常見的黃酮類化合物。研究發現，在WRL-68細胞中，芹菜素能夠劑量依賴性的抑制3 - 羥基-3 - 甲基 - 戊二酸單酰輔酶還原酶 (HMGCR)和固醇調節元件結合蛋白-2 (SREBP-2) 信使RNA和蛋白的表達及其啟動子的轉錄活性。綜上所述，在肝細胞中，芹菜素能有效抑制HMGCR和SREBP-2的表達，從而達到降低膽固醇的效果。 / 總括而言，本研究表明在去除卵巢的祼鼠模型中，短期熱量限制能有效抑制乳腺癌細胞的生長和芹菜素能有效抑制HMGCR和SREBP-2的表達。 / Non-communicable diseases (NCD) are one of the leading causes of mortality in the developed and under-developing countries. Diet is a major risk factor of NCD. In the present study, effects of diet modification on breast cancer development and cholesterol metabolism were investigated. / In the first part of this study, the effect of chronic and short-term calorie restriction (CR) on breast tumor growth in ovariectomized nude mice was investigated. The calorie-restricted dietary regimen limited the total fat intake only. 14 week-old ovariectomized female nude mice were randomly assigned to ad libitum fed (AL), 20%CCR (17-week 80% of AL), 30%CCR (17-week 70% of AL), 35%CCR (17-week 65% of AL) and short-term CR (3.5-week 65% of AL followed by 13.5-week 100% AL consumption) groups. Starting from 10 weeks after transplant of cells, the tumor volumes in all calorie-restricted groups were significantly smaller (P < 0.05) than that in ad libitum control. At sacrifice, the tumor weight in short-term CR was significantly smaller (P < 0.05) than that in ad-libitum control after normalized with body weight. This indicated that short-term CR could suppress tumor in this model. / In the second part of this study, the effect of apigenin on cholesterol metabolism was investigated. Apigenin is one of the most abundant flavonoids. In the present study, we investigated the effect of apigenin on several cholesterol-related gene expression in hepatic cells. In WRL-68 cells treated with apigenin, promoter transcription activity, mRNA and protein expression of HMGCR and SREBP-2 were significantly decreased in a dose-dependent manner. Taken together, we concluded that apigenin inhibited HMGCR and SREBP-2 gene expressions in hepatic cells, which might elicit the hypocholesterolemic effects. / In conclusion, our study has demonstrated that short-term CR could significantly block the breast tumor growth in a mice model and apigenin could inhibit the expression of HMGCR and SREBP-2 in liver cell lines. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wong, Tsz Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 83-99). / Abstracts also in Chinese. / ACKNOWLEGEMENTS --- p.i / ABSTRACT --- p.ii / 摘要 --- p.iv / list of abbreviations --- p.v / list of figures --- p.vii / list of tables --- p.IX / TABLE of CONTENTS --- p.X / Chapter 1 --- CHAPTER 1 --- p.1 / General Introduction --- p.1 / Chapter 1.1 --- Calorie Restriction and the Prevention of Postmenopausal Breast Cancer --- p.2 / Chapter 1.1.1 --- Breast Cancer --- p.2 / Chapter 1.1.2 --- Epidemiology of Excess Body Weight and Cancer Risk --- p.3 / Chapter 1.1.3 --- Calorie Restriction and Cancer Prevention --- p.7 / Chapter 1.1.4 --- Mechanistic Targets of Calorie Restriction --- p.8 / Chapter 1.1.4.1 --- Effect of Calorie Restriction on Estrogen --- p.8 / Chapter 1.1.4.1 --- Effect of Calorie Restriction on Cell Cycle Regulation --- p.12 / Chapter 1.1.4.1 --- Effect of Calorie Restriction on Apoptosis --- p.14 / Chapter 1.2 --- Effect of Apigenin on Cholesterol Homeostasis --- p.17 / Chapter 1.2.1 --- Cardiovascular Disease and Blood Cholesterol --- p.17 / Chapter 1.2.2 --- Molecular Regulation of Cholesterol Metabolism --- p.21 / Chapter 1.2.2.1 --- HMG-CoA Reductase --- p.21 / Chapter 1.2.2.2 --- CYP7A1 --- p.24 / Chapter 1.2.2.3 --- Apolipoprotein A-1 --- p.26 / Chapter 1.2.2.4 --- Low Density Lipoprotein Receptor --- p.29 / Chapter 1.2.2.5 --- Sterol Regulatory Element Binding Proteins --- p.31 / Chapter 1.2.3 --- Flavonoid and its Association with Cholesterol Metabolism --- p.36 / Chapter 1.2.4 --- Apigenin: A Potential Alternative --- p.39 / Chapter 2 --- CHAPTER 2 --- p.41 / MATERIALS AND METHODS --- p.41 / Chapter 2.1 --- Chemicals and Materials --- p.41 / Chapter 2.1.1 --- Chemicals --- p.41 / Chapter 2.1.2 --- Plasmids --- p.41 / Chapter 2.2 --- Cell Culture --- p.41 / Chapter 2.2.1 --- Maintainance of Cells --- p.41 / Chapter 2.2.2 --- Preparation of Cell Stock --- p.42 / Chapter 2.2.3 --- Cell Recovery from Liquid Nitrogen Stock --- p.42 / Chapter 2.3 --- Measurement of Cell viability --- p.43 / Chapter 2.4 --- Semi-Quantitative and Quantitative RT-PCR Assay --- p.43 / Chapter 2.4.1 --- RNA Isolation and cDNA Synthesis --- p.43 / Chapter 2.4.2 --- Quantitative Real Time PCR Assay --- p.43 / Chapter 2.4.2.1 --- Real Time PCR Using TaqMan Probe --- p.43 / Chapter 2.4.2.2 --- Real Time PCR Using SYBR Green Dye --- p.44 / Chapter 2.4.2.3 --- Statistical Analysis of 2⁻ΔΔ{U+A7F0}{U+1D40} Comparative Gene Expression --- p.44 / Chapter 2.5 --- Western Blot Analysis --- p.46 / Chapter 2.6 --- Measurement of Promoter Activity --- p.46 / Chapter 2.6.1 --- Plasmid Preparation --- p.46 / Chapter 2.6.2 --- Transient Transfection and Dual-Luciferase Assay --- p.47 / Chapter 2.7 --- Animal Experiment Design --- p.47 / Chapter 2.7.1 --- Animal Model and Dietary Regimens --- p.47 / Chapter 2.7.2 --- Tissue Sample Collection --- p.50 / Chapter 2.7.3 --- Plasma Estradiol Determination --- p.50 / Chapter 2.7.4 --- Protein and RNA extraction --- p.50 / Chapter 2.8 --- Statistical Analysis --- p.50 / Chapter 3 --- Chapter 3 --- p.51 / EFFECT OF CHRONIC AND short-term calorie restriction on breast tumor growth in ovariectomized nude mice --- p.51 / Chapter 3.1 --- Introduction --- p.51 / Chapter 3.2 --- Objectives --- p.52 / Chapter 3.3 --- Results --- p.53 / Chapter 3.3.1 --- Food Intakes, Body, Liver and Uterus Wet Weights of the Mice --- p.53 / Chapter 3.3.2 --- Tumor Development --- p.57 / Chapter 3.3.3 --- Plasma Estradiol Level --- p.62 / Chapter 3.3.4 --- Estradiol Responsive Gene expression in Tumors --- p.63 / Chapter 3.3.5 --- Cell Apoptotic and Cell Cycle-Regulated Protein expression in Tumors --- p.65 / Chapter 3.4 --- Discussion --- p.67 / Chapter 4 --- CHAPTER 4 --- p.69 / Apigenin inhibits the expression of hmg-coa reductase and srebp-2 in hepatic cells --- p.69 / Chapter 4.1 --- Introduction --- p.69 / Chapter 4.2 --- Objectives --- p.70 / Chapter 4.3 --- Results --- p.70 / Chapter 4.3.1 --- Effect of Apigenin on Cell Viability --- p.70 / Chapter 4.3.2 --- Effect of Apigenin on HMGCR, CYP7A1, LDLR, ApoA-1, SREBP-1 and SREBP-2 mRNA expressions --- p.72 / Chapter 4.3.3 --- Effect of Apigenin on HMGCR, LDLR, ApoA-1 and SREBP-2 Promoter Transcription Activity --- p.75 / Chapter 4.3.4 --- Effect of Apigenin on HMGCR, SREBP-1 and SREBP-2 Protein Expression --- p.77 / Chapter 4.3.5 --- Role of Estrogen Receptor in Apigenin induced SREBP-2 Inhibition --- p.79 / Chapter 4.4 --- Discussion --- p.80 / Chapter 5 --- CHAPTER 5 --- p.82 / SUMMARY --- p.82 / References --- p.83

Le tissue adipeux (TA) est un organe complexe specialisé dans le stockage et la libération d'énergie sous forme de lipides. Cet organe adipeux est essentiel pour le maintien de l'homéostasie énergétique. Les adipocytes sont les cellules prototypiques du TA. Elles se forment durant la différenciation de précurseurs, un processus appelé adipogenèse. L'adipogenèse est intimement associée à la synthèse des acides gras et de triglycérides lors de la lipogenèse. Néanmoins, divers facteurs peuvent perturber l'adipogénèse et la lipogenèse, contribuant au dysfonctionnement du TA et au développement des maladies métaboliques. Le but de cette thèse a été d'étudier la lipogenèse dans le contexte du stress du réticulum endoplasmiques (SRE), de la restriction calorique et du vieillissement. Dans le projet A, nous avons montré que l'exposition d'adipocytes à un SRE aigu inhibe l'expression des gènes liés à la lipogenèse et empêche l'incorporation du glucose dans les lipides. En plus, l'exposition des préadipocytes à un SRE chronique, détériore à la fois la lipogenèse et l'adipogenèse. Par contre, pour les adipocytes, un SRE chronique mais modéré n'a pas d'effet évident sur la lipogenèse. Ces effets du SRE pourraient contribuer à la détérioration de la fonction de TA vue dans l'obésité. La capacité du TA à stocker des lipides diminue avec l'âge, probablement à cause de l'accumulation de cellules sénescentes ou un SRE plus élevé. Dans le projet B, nous avons étudié la capacité lipogénique du TA humain en relation à la sénescence et aux marqueurs du SRE au sein d'une cohorte de femmes obèses jeunes ou âgées. Tandis que l'expression des principaux marqueurs de la sénescence était augmentée dans le TA des femmes âgées, l'expression génique des enzymes de lipogenèse et des chaperonnes était diminuée dans le TA des personnes âgées. Ces résultats étaient partiellement retrouvés dans les adipocytes différenciés in vitro des mêmes individus ce qui suggère une moins bonne capacité à faire face au SRE lors du vieillissement. Le régime à très basses calories (VLCD) est souvent prescrit en première intention pour une rapide perte de poids. L'amélioration de la sensibilité à l'insuline se voit dès 2 jours de VLCD. Néanmoins, on ne sait quasiment rien des modifications métaboliques du TA survenant durant les premiers jours. Dans le projet C, nous avons donc comparé les réponses métaboliques et inflammatoires du TA sous-cutané précocément (2 jours) et plus tardivement (28 jours) lors d'un VLCD. A 2 jours de régime, l'expression des gènes lipolytiques était augmentée, alors que l'expression des gènes lipogéniques était diminuées. Les marqueurs d'inflammation n'étaient pas changés dans le TA. Néanmoins, les changements d'expression dans le TA lors de la phase précoce du régime ne pouvait pas expliquer l'effet de ce régime court à l'amélioration de la sensibilité à l'insuline. Dans la phase tardive, l'expression des gènes impliqués dans la lipogenèse et la ß-oxydation était largement réduite, tandis que l'expression des marqueurs inflammatoires était augmentée. Nous avons donc montré que les réponses métaboliques et inflammatoires du TA sous-cutané à 2 jours et 28 jours de VLCD sont différentes. Dans le projet D, nous avons comparé et défini les effets de la restriction calorique modérée sur la physiologie des préadipocytes et des adipocytes différenciés in vitro chez des jeunes obèses ou des personnes âgées obèses. De façon surprenante, on n'a observé aucun effet de l'intervention sur le métabolisme des préadipocytes dans les deux groupes. Par contre, un effet bénéfique de l'intervention sur le métabolisme adipocytaire n'a été observé que chez les personnes âgées. Nos données montrent donc qu'une restriction calorique modérée peut avoir un effet positif sur le métabolisme adipocytaire des séniors. Pour conclure, cette thèse montre que la lipogenèse dans le TA humain peut être inhibée par le SRE, la restriction calorique sévère et le vieillissement. / Adipose tissue (AT) is a complex organ specialised in safe storage and release of energy as lipids. The adipose organ is therefore essential for the maintenance of energy homeostasis. The prototypical cells of AT are adipocytes, emerging from the precursors in a process called adipogenesis. Adipogenesis itself is tightly connected with lipogenesis, i.e. with the synthesis of fatty acids and triglycerides. Various stimuli can disturb adipocyte differentiation and lipogenesis and thus contribute to AT dysfunction and development of associated metabolic diseases. This thesis was focused on the investigation of lipogenesis in the context of endoplasmic reticulum stress (ERS), calorie restriction and aging. In Project A, we showed that exposition of adipocytes to high acute ERS inhibits expression of lipogenic genes and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to ERS impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in adipocytes. These effects of ERS could therefore contribute to the worsening of AT function seen in obesity. The capacity of AT to store lipids decreases in aging, possibly due to the accumulation of senescence cells or higher ERS. In Project B, we investigated lipogenic capacity of human AT in relation to senescence and markers of ERS. AT and adipose cells from young and elderly women were investigated. While mRNA expression of major senescent markers was increased in AT from the elderly compared to young individuals, mRNA expression of lipogenic enzymes and chaperones was decreased in AT from elderly individuals. These results were also partly observed in vitro in differentiated adipocytes from AT of the same individuals suggesting the reduced capability to cope with ERS in aging. Very-low calorie diet (VLCD) is first line lifestyle intervention to achieve rapid weight loss. The improvement of whole body insulin sensitivity can be seen as soon as after 2 days of VLCD. However, little is known about AT metabolic changes in those early days. Thus, in Project C, we compared metabolic and inflammation-related characteristics of subcutaneous AT in the early (2 days) and later (28 days) phase of a VLCD. In the early phase of VLCD, the expression of lipolytic genes was increased, whereas the expression of lipogenic genes was suppressed. The inflammatory markers remained unchanged in AT. The changes in AT gene expression in the early phase of VLCD could not explain the effect of short calorie restriction on the improvement of insulin sensitivity. At the later phase, expression of genes involved in lipogenesis and ß-oxidation was markedly suppressed, whereas the expression of inflammatory markers was increased. Thus, we found that the early and later phases of VLCD differ with respect to metabolic and inflammatory responses in subcutaneous AT. In Project D, we compared and defined the effects of moderate calorie restriction on preadipocytes and in vitro differentiated adipocytes in two groups of obese men: juniors and seniors. We did not observe any effect of the intervention on metabolism of preadipocytes in either group. However, we observed an intervention-driven improvement in adipocyte metabolism selectively in the group of seniors. Therefore, our data suggest that moderate calorie restriction could initiate positive changes in metabolism of adipocytes in seniors. In conclusion, this thesis brought several pieces of evidence that lipogenesis in human AT can be inhibited by ER stress, severe caloric restriction and aging.

Obesity is a disease of major proportion in the United States. The Surgeon General has identified obesity as a national health problem that affects approximately 34 million Americans. The aim of this study was to investigate the very-low-calorie diet, Optifast 70. Measurements for resting energy expenditure (REE} and body composition via circumference measurements (CBF} and infrared photospectromerty (NIR} with a Futrex 5000 were collected at weeks 1, 7, 13, 19, and 25. Biochemical data, including serum chemistry panel (SMA-12} and complete blood count (CBC}, were collected on weeks 1, 5, 9, 13, 17, 21, and 25. Lipid profiles were drawn on weeks 1 and 25. Participants ranged in age from 27 to 64. Subjects' mean body mass loss was -20.4 kg ± 6.6 kg with a maximum body mass loss of -33.23 kg and minimum body mass loss of -9.770 kg. Mean loss in body fat mass using infrared photospectrometry as a measurement was -13.4 kg; mean loss of lean body mass was -4.2 kg. A significant change was noted in resting energy expenditure over the course of the diet, and a positive correlation was identified between loss of body mass and resting energy expenditure. No significant correlation was identified between the loss of lean body mass or body fat mass and its relationship to resting energy expenditure. Both circumference and infrared body fat measurements showed a positive correlation as the loss in body mass increased, making their reliability better as subjects approached desirable weight. In examining biochemical data, only cholesterol showed a significant change over the course of the diet; all other parameters remained within normal limits. Variations in patients' lipid profiles were identified, but no significant changes were noted.